This application seeks continuing funding for the Hepatitis C Cooperative Research Center (HC-CRC) at the University of Southern California (USC) to coordinate and advance research toward understanding the replication infection. HCV is currently the major cause of chronic hepatitis in this country. Options for therapeutic intervention and prevention are limited. Continued funding will facilitate and expand the long-standing collaborative research activities at the USC HC-CRC. Four specific projects are proposed: 1. Study of the effects of HCV proteins on host functions. Emphasis will be placed on the effects of HCV proteins on the interferon activities, particularly the effect of viral E2 and NS5a proteins on host proteins mediating interferon actions. 2) Study of the immune modulation by the HCV core protein. By using an experimental model of adenovirus infection of mouse, we will study the effects of HCV core protein on TNF signaling, induction of cytotoxic T cells, antigen presentation and NK cell function in the liver. 3) Study of the mechanisms of HCV replication. We will develop in vitro cell culture systems for studying HCV replication. We will also study a novel HCV gene product discovered in Dr. Jing-Hsiung Ou's laboratory. 1) Study of the role of E2 and NS5a sequence variations in interferon resistance in patient populations. Furthermore, we will also study the role of NS5b mutations in the clinical resistance to ribavirin. These projects are expected to contribute to the understanding of viral pathogenesis and further improvement in therapies for HCV.